The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28–75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73–0.92; p = 0.001) per 1 standard deviation (SD) change in log_e total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78–0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69–1.38; p = 0.900) for FLI and 1.14 (0.81–1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

中文翻译：

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PREVEND研究中循环总胆红素和非酒精性脂肪肝的风险：观察结果和孟德尔随机研究

循环中总胆红素与非酒精性脂肪性肝病（NAFLD）之间的关系尚不确定。我们旨在评估总胆红素与新发NAFLD风险的关联，并使用孟德尔随机（MR）研究调查与该关联相关的任何因果关系。在前瞻性研究中对3824名参与者（年龄在28-75岁之间）进行了血浆前血浆总胆红素水平的测定，这些患者没有预先存在的心血管疾病或NAFLD。使用基于生物标志物的算法，脂肪肝指数（FLI）和肝脂肪变性指数（HSI）评估了NAFLD事件。评估了NAFLD的赔率（OR）（95％置信区间）。位于UDP-葡糖醛酸糖基转移酶（UGT1A1）位点的遗传变体rs6742078被用作工具变量。参加者的平均随访时间为4.2年。FLI估计NAFLD的多变量校正OR（95％CI）为434例（0.73-0.92；对数_e总胆红素每变化1标准偏差（SD），p  = 0.001）。根据HSI（452例）估计，NAFLD的相应校正OR（95％CI）为0.87（0.78-0.97；p  = 0.012）。rs6742078变体解释了20％的胆红素变异。1 SD基因升高的总胆红素水平的OR（95％CI）对于FLI为0.98（0.69–1.38; p  = 0.900），而对于BLI为1.14（0.81–1.59; p = HSI的= 0.451）。根据MR分析，总胆红素水平升高与NAFLD风险降低无因果关系。观察关联可能是由偏见驱动的，例如无法测量的混杂和/或反向因果关系。但是，由于统计能力低，必须进行大规模调查才能得出明确的结论。